The plasma of two hypertensive patients with renin-secreting Wilms' tumor contained large amounts of an unusual renin-like enzyme, whose behavior on Sephadex columns indicates a higher molecular weight than normal plasma renin (hence the term, "big renin"). Big renin generates angiotension from human renin substrate, and resembles normal renin in many enzymatic and immunologic properties. Unlike normal renin, big renin exerts only a fraction of its potential enzymatic activity unless it is activated by preliminary exposure to acid (pH 3), or by controlled treatment with trypsin or pepsin. In 30 patients studied thus far, big renin has been found in plasma of 5 patients with hypertension and high plasma renin activity (3 Wilms' tumor and 2 with malignant or renovascular hypertension). Big renin was consistently found in patients with diabetic nephropathy and less commonly in other renal disorders. When big renin is the only form of renin present in plasma, conventional measurements of PRA may suggest a "low-renin" hypertensive state. We propose to screen additional hypertensive patients and to examine plasma and renal tissue (when surgery is indicated) from patients with renal tumors and other disorders, in order to define the pathological conditions which lead to the release of big renin, and to elucidate the role of big renin in the pathogenesis of hypertension or other clinical states. As sources of big renin are found, its physical and enzymatic properties will be further examined.